Download Angiotensin

Advantages of renin-angiotensin
system blockade in the treatment
of cardiovascular disease
V. Gerc
Clinic for Heart Disease and
Rheumatism
Sarajevo
The cardiovascular continua in
cardiovascular disease
The pathophysiological continua in
cardiovascular disease
Angiotensin II is central to
atherosclerotic mechanisms
Oxidative Stress
Inflammation
NAD(P)H oxidase activity ↑
Vascular permeability ↑ Leucocyte infiltration ↑
Reactive oxygen species ↑
Activation of signalling pathways
LDL peroxidation ↑
LDL peroxidation ↓
Production of
inflammatory mediators
Angiotensin II
Nitric oxide ↓
Proliferation of VSMCs
Vasoconstriction
PAI-1 activation
Platelet aggregation
Endothelial dysfunction
Matrix deposition
MMP activation
Tissue remodelling
Schmieder et al. Lancet 2007;369:1208−1219
Vascular Risk Factors and Endothelial
Dysfunction
Role of oxidative stress:
Angiotensin II
Smoking
Hypertension
Homocysteine
oxLDL
Diabetes
Bradykinin/NO
-
oxidative stress
-
Endothelial Dysfunction
mod. from Gibbons GH, Clin Cardiol 20 (1997)
Antioxidants (?)
Long-term cardiovascular
effects of angiotensin II
Metabolism of the Renin-Angiotensin System
Component
Half-life in
circulation
Degrading enzyme(s)
Renin
15–20 min
—
Angiotensinogen
4–16 h
Renin
Angiotensin I
1–2 min
Angiotensinconverting enzyme
Angiotensin II
Seconds
Aminopeptidase A,
endopeptidase,
Prolylcarboxypeptidase
Mechanism of action of angiotensinconverting enzyme inhibitors
EFFECTS OF ANGITENSIN II
  vasoconstriction (”afterload” )
  reabsorption of Na+ and water (“preload” )
  coronary constriction
  syntesis of cellular proteins (HLV)
  fibroblastic hyperplasia (myocardial fibrosis)
  apoptosis of myocites
  diastolic dysfunction of the heart
EFFECTS OF ANGIOTENSIN II
  sympathetic,  vagal activity
  adrenocortex ( catecholamine, aldosterone)
  endothelial dysfunction
  PAI-1 ( fibrinolysis)
  tissue factor
  proliferation and migration of smooth
muscles
Potential pathogenic properties
of Angiotensin II
• Heart
• Myocardial hypertrophy
• Interstitial fibrosis
Potential pathogenic properties
of Angiotensin II
• Coronary Arteries
• Endothelial dysfunction with decreased
release of nitric oxide
• Coronary constriction via release of
noradrelanine
• Increased oxidative stress; oxygen derived
free radicals formed via NADH
• Promotion of inflamatory response and
atheroma
Potential pathogenic properties
of Angiotensin II
•
•
•
•
•
Kidneys
Increased intraglomerular pressure
Increased protein leak
Glomerular growth and fibrosis
Increased sodium reabsorption
Potential pathogenic properties
of Angiotensin II
• Adrenals
• Increased formation of aldosterone
Potential pathogenic properties
of Angiotensin II
• Coagulation system
• Increased fibrinogen
• Increased PAI-1
Inhibition of the RAS
• Inhibition of the RAS is established for
the treatment and now prevention of a
wide range of cardiovascular disease.
The basic concept hinges on the
adverse effects of excess angiotensin II
and increase protective bradykinin.
Renin – Angiotensin - Aldosterone system:
where inhibitors act
Dual role of ACE inhibitors, both preventing
and treating cardiovascular disease
Pharmacodynamic
effects of ACEI
Hemodynamic: vasodilation (AII, BK, PGI, NO)
Sympatholytic: Ach NA
Endothel: PGI, NO, AII, endothelin
Antiproliferative: AII, aldo, c-fos, c-myc
Antithrombotic: PAI-1
Antiatherogenic: the above + antioxidants
Indications for ACEI, based on
trial data
•
•
•
•
1.Heart failure, all stages
2. Hypertension
3.AMI, postinfarct LV dysfunction
4.Nephropathy, nondiabetic and
diabetic
• 5. Diabetes type 2, lessens new
microalbuminuria and LV hypertrophy
Antiatherosclerotic effect of
LISINOPRIL
Blood pressure
Inflammation
Endothelian dysf.
ACE
Nitric oxide
Growth of the plaque
Fibrinolysis
tPA
PAI-1
Reduction of cardiovascular
events
Oxidative stress
Pleiotropic effects of renin-angiotensin
system blockers
Pleiotropic effects
Statins
ACEI
Early effects
(hours, days)
LDL,TG;HDL
NOS, O-
AII, BK, PG
O-
Intermediary
effects
(weeks)
Viscosity
 Tr aggregation
PAI-1
Fibrinolysis
 Tr activation
BMP-2
Late effects
(months)
Cell migration,
proliferation;
stabilisation of the
plaque
Cell migration,
proliferation;
stabilisation of the
plaque
Angiotensin-converting enzyme inhibitors in
hypertensive patients at high cardiovascular risk
ACEI
ACE inhibitors in hypertension
• ACEI are effective as monotherapy in
BP reduction in most patients. There
are few side effects and contraindication
ACE inhibitors in hypertension
• A particulary attractive combination is
that with diuretics, because diuretics
increase circulating renin activity and
angiotensin II levels, wich ACEI
counterregulate by inhibiting the
conversion of angiotensin I to
angiotensin II.
RAAS, ACEIs, and ARBs: Summary
• RAAS is a major regulator of CV and renal function
• RAAS blockade
– Reduces BP
– Exerts antiatherosclerotic effects
– Delays or avoids onset of T2DM
• ACEIs and ARBs are the major RAAS blockers in use
• ACEIs do not inhibit Ang II formation by non-ACE pathways
• ACEIs block AT1 and AT2 receptors, whereas ARBs inhibit
AT1 receptors and leave AT2 receptors open for stimulation
Schmieder RE et al. Lancet. 2007;369:1208-19.
Role of ARB in the treatment of
cardiovascular diseases, with a
special reference to
LOSARTAN
Arguments favoring development of
ARBs
• ACE inhibitors are not specific
• ACE inhibitors do not provide
complete blockade of RAS
• Alternative pathways for angiotensin
II formation
• Significant incidence of cough
Arguments favoring development of
ARBs
• ACE inhibitors are not specific
• ACE inhibitors do not provide
complete blockade of RAS
• Alternative pathways for angiotensin
II formation
• Significant incidence of cough
Angiotensin II formation in the heart mediated by
chymase v.s. formation mediated by angiotensin
converting enzyme
ACE mediated
Chymase mediated
A II formation, %
100
80
60
40
20
0
Mouse
Rabbit
Rat
Balcells E, et al. Am J Physiol. 1997;273:H1769–H1774.
Dog
Human
“Escape” of angiotensin II
despite ACE inhibition
100
80
Plasma ACE 60
(nmoL/mL/min)40
20
0
*
*
*
*
*
*
*
24 h
1
2
3
4
5
6
*
30
20
Plasma Ang II
(pg/mL)
10
*
0
Placebo
Biollaz J, et al. J
Cardiovasc
Pharmacol.
1982;4(6):966-972.
4h
Hospital
Months
*P <.001 vs
placebo
Inhibition of the RAS
• ARBs directly block the angiotensin II
receptor (AT1), thereby largely avoiding
the side effects of excess bradykinin
such as cough and angioedema.
Mechanism of action of angiotensin
receptor blockers
Effects of Angiotensin II upon AT1 i AT2
receptors
AT1
Vasoconstriction
Aldosteron release
Oxidative stress
Vasopresin release
Activation of SNS
Inhibition of renin release
Renal reabsorption of Na+ i H2O
Cell growth and proliferation
Siragy H. Am J Cardiol. 1999;84:3S-8S.
AT2
Vasodilation
Antiproliferative effect
Apoptosis
Antidiuresis/antinatriuresis
Bradykinin formation
Release of NO
ARBs currently available for clinical use
Generic name
Trade name
Drug company
Losartan
Losartan H
Tenlop
Tenlop H
Bosnalijek
Valsartan
Diovan, Tareg,
Nisis
Novartis
Irbesartan
Aprovel, Avapro,
Karvea
Bristol-Myers,
Squibb, Sanofi
Candesartan
Atacand, Kenzen,
Blopress
AstraZeneca/
Takeda
Telmisartan
Micardis, Pritor
Glaxo Smith Kline
Eprosartan
Teveten
Glaxo Smith Kline
Olmesartan
Benycar, Daiichi
Sankyo
Pharmacology of Angiotensin Receptor Blockers
Half-life,
h
Bio
availabilit
y%
Volume of
distributio
n
Renal/
hepatic
clearance,
%
Candesartan
9
15
0.13 L/kg
60/40
Eprosartan
5
13
13 L
30/70
Irbesartan
11–15
60–80
53–93 L
1/99
2
33
34 L
10/90
6–9
−
12 L
50/50
Olmesartan
10–15
28
17 L
45/55
Telmisartan
24
42–58
500 L
1/99
6
∼25
17 L
30/70
Drug
Losartan
E-3174
Valsartan
ARBs currently available for clinical use
Drug
Recommended
initial dosage
Dosage range
Tablet/capsule
Losartan,
Tenlop
50 mg once daily
25-50 mg, once
daily, or 100 mg
once daily
tablet
12,5, 50, 100 mg
Valsartan
80 mg once daily
80-320 mg once
or twice daily
capsule
80,160 mg .
Irbesartan
150 mg once daily
150-300mg once
daily
tablet
75,150, 300 mg
Candesartan
8 mg once daily
8-16 mg once or
twice daily;32 mg
once daily
tablet
4,8,16,32 mg
Eprosartan
400 mg once daily
400-800 mg once
daily
tablet
200, 400 mg
Telmisartan
40 mg once daily
40-80 mg once
daily
tablet 40,80 mg
Olmesartan
20 mg once daily
20-40 mg once daily
tablet 20,40 mg
ARBs
Indications
• Hypertension
• Heart failure
• Secondary prevention following
myocardial infarction
• Diabetic nephropathy
• Proteinuria/microalbuminuria
• Left ventricle hypertrophy
• Atrial fibrilation
• Cough caused by ACEI
Losartan and
hypertension
Studies with Losartan
The Losartan Heart Failure
Study (ELITE)
n=722
The Losartan Hypertension
Survival Study (LIFE)
n=9194
The Losartan Heart Failure
Survival Study (ELITE II)
n=3152
The Losartan Post-MI Survival
Study (OPTIMAAL)
n=5000
The Losartan Renal Protection
Study (RENAAL)
n=1520
19,588
Comparison of efficacy of candesartan
and losartan in the treatment of
hypertension : results at trough
Andersson, 1998
DP
mmHg
Plac
4
Los
50
CC
8
CC
16
SP
mmHg
4
0
0
-4
-4
-8
*
-12
*#
-16
-12
-16
-20
-20
85
Los
50
CC
8
CC
16
-8
*
n
Plac
83
82
84
*
*
*
* p<0.001 vs plac ; # p>0.05 vs
Los
Comparison of efficacy of candesartan
and losartan in the treatment of
hypertension : results at peak
DP
mmHg
Andersson, 1998
SP
mmHg
Plac
4
Los
50
CC
8
CC
16
4
0
0
-4
-4
-8
-8
*
-12
-16
-16
-20
-20
n
85
83
82
Los
50
CC
8
CC
16
-12
*
*
Plac
84
*
*
* p<0.001 vs
*
plac
Comparison of efficacy of ARBs and
amlodipine in the treatment of mild and
moderate hypertension
Los 50
Amlo 10
Vals 80
0
0
-4
-4
mmHg -8
-8
-12
-12
Amlo 5
SP
DP
-16
-16
Irbe 75 - 300
CC 8 Amlo 10 Plac
Amlo 2.5 - 10
0
0
-4
-4
mmHg -8
-8
-12
-12
-16
-16
Comparison of efficacy of ARBs and enalapril
in the treatment of mild and moderate
hypertension
0
Los 50
Enal 20
0
-4
-4
mmHg -8
-8
-12
-12
-16
-16
0
mmHg
Vals 80
Enal 20
SP
Irbe 75-300 Enal 10- 40
0
-4
-4
-8
-8
-12
-12
-16
-16
DP
CC 4- 8
Enal 10-20
Comparison of efficacy of ARBs and
hydrochlorothiazide in the treatment of
hypertension
Los 50
HCTZ 12.5
Vals 80
0
0
-4
-4
mmHg -8
-8
-12
-12
-16
-16
CC 8
HCTZ 25
0
-4
mmHg -8
-12
-16
SP
DP
HCTZ 25
Comparison of efficacy of ARBs and atenolol
in the treatment of mild and moderate
hypertension
Los 50
Atenolol 50
0
0
-2
-2
-4
-4
mmHg -6
-6
Irbes Atenolol
75-150 50-100
-8
-8
-10
-10
-12
-12
-14
-14
SP
DP
Dijastolni P.
Angiotensin receptor blockers and
hypertension: meta-analysis
Meta-analysis of CV events with ARBs
vs comparators
Blood Pressure Lowering Treatment Trialists’ Collaboration
4 trials; N = 16,791
1.2
1.0
Relative risk of
event with ARB
vs comparator
0.8
0.6
Stroke
CHD
Heart failure Major CV event
BPLTTC. Lancet. 2003;362:1527-35.
Efficacy vs. Tolerability
AT1- Receptor Antagonists
excellent
Tolerability
50 %
low
Therapeutic
Window
DOSE
Compliance With Antihypertensive
Treatment at 1 Year
*
64
Compliance at 1 Year (%)
65
60
58
55
50
50
45
40
35
0
43
38
Thiazide
Diuretics
Beta
Blockers
CCBs
ACE
Inhibitors
ARBs
ARBs:
Evolution
of protective
benefits
ARBs:
Evolution
of protective
benefits
s↓BP
tifeneb
↓BP
evitcetorp fo noitulovE :sBRA
↓Stroke
↓Stroke
PB↓
↓Heart
failure
↓Heart
failure ekortS↓
↓Renal
eruldysfunction
iaf tdysfunction
raeH↓
↓Renal
↑Glycemic
control
noitcnufsyd lan
eR↓↑Glycemic
control
lortnoc cimecylG↑
)?( DHC↓
↓CHD
(?) (?)
↓CHD
Combination antihypertensive therapy and
cardiovascular event rate: amlodipine and
renin-angiotensin system blockade
ACCOMPLISH: Exceptional Control Rates
with Initial Combination Therapy
90
Control rate (%)
80
78.5
81.7
70
60
50
40
30
37.2
37.9
ACEI / HCTZ
CCB / ACEI
N=5733
N=5713
20
10
P<0.001 at 30 months follow-up
Control defined as <140/90 mmHg
Baseline
Control Rates
Kaplan Meier for Primary
Endpoint
Cumulative event rate
ACEI / HCTZ
20% Risk Reduction
650
CCB / ACEI
526
p = 0 .0002
Time to 1st CV morbidity/mortality (days)
HR (95% CI): 0.80 (0.72, 0.90)
I
Primary Endpoint and
Components
Risk Ratio
(95%)
Composite CV mortality/morbidity
0.80 (0.72–0.90)
Cardiovascular mortality
0.81 (0.62-1.06)
Non-fatal MI
0.81 (0.63-1.05)
Non-fatal stroke
0.87 (0.67-1.13)
Hospitalization for unstable angina
0.74 (0.49-1.11)
Coronary revascularization procedure
0.85 (0.74-0.99)
Resuscitated sudden death
1.75 (0.73-4.17)
0.5
Favors
CCB / ACEI
1.0
2.0
Favors
ACEI / HCTZ
Clinical trials of RAAS manipulation with ARBs
Diabetes and/or renal disease
CAD/MI
VALIANT
OPTIMAAL
Val-PREST
RENAAL
IDNT
IRMA-2
ABCD-2V AMADEO
DETAIL
MARVAL
Stroke
SCOPE
MOSES
Hypertension
VALUE
SCOPE
TROPHY
LIFE
CHF
ELITE 1 and 2
Val-HEFT
CHARM
Dzau V. J Hypertens. 2005.
Dahlof B. Am J Cardiol. 2007.
Barnett AH et al. N Engl J Med. 2004.
Bakris G et al. ASH 2007 Scientific Sessions.
LIFE study
• The Losartan Intervention For Endpoint reduction in
hypertension study
• Prospective, multinational, double-blind,
controlled, random study, intention-to-treat
study
• 9.193 patients with hypertension and ecg signes of
LVH
• Losartan compared to atenololom
Dahlöf B. et al, Lancet 2002.; 359:995-1003.
LIFE: Losartan and atenolol reduced
comparably blood pressure
180
Atenolol
Losartan
160
Systolic
mmHg
140
120
Mean arterial pressure
100
Diastolic
80
60
40
0
6
12
18
24
30
36
Duration (months)
Dahlöf B et al Lancet 2002;359:995–1003.
42
48
54
LIFE: LVH Regression and Primary
Endpoint
16
-2
14
-4
-6
12
4.4%
10
-8
9.0%
-10
-12
-14
-16
-18
Composite of CV Death,
Stroke and MI
Sokolow-Lyon
Voltage
Proportion of Patients with
First Event (%)
Change from Baseline (%)
Cornell Voltage-Duration
Product
0
10.2%
P < 0.0001
15.3%
P < 0.0001
8
6
4
Adjusted Risk Reduction:
13.0%, P = 0.021
2
0
0 6 12 18 24 30 3642 48 5460 66
Months
Atenolol
Dahlöf B et al. Lancet. 2002;359:995-1003.
Losartan
LIFE – significant regression of LVH in
comparison to baseline values
Cornell Product
Sokolow-Lyon
Mean changes in the baseline values (%)
0
-2
-4
losartan
4.4 %
-6
atenolol
-8
-10
-12
-14
-16
-18
9.0 %
10.2 %
p<0.0001
15.3 %
p<0.0001
Reduction of left ventricular mass stratified
according to various antihypertensive regimens
reduction in left ventricular
mass LV (%)
20
*
15
*
**
10
5
0
*p<0.05; **p<0.001 vs beta-blocker
Diuretics
Betablockers
Calcium
antagonist
ACE
inhibitors
ARBs
Klingbeil et al Am J Med 2003
Losartan reduces CV complications
with equal antihypertensive efficacy
% of patients with the first signes
of hypertensive complications
16
14
Cardiovascula death, stroke and myocardial
infarction miokarda
Atenolol
13%
12
10
Losartan
8
6
4
2
Adjusted risk reduction
Non-adjusted risk reduction
13.0%, p=0.021
14.6%, p=0.009
0
Months
0
No. of patients
Losartan (n) 4605
with risk
Atenolol (n) 4588
6
12
18
24
30
36
42
48
54
60
66
4524
4494
4460
4414
4392
4349
4312
4289
4247
4205
4189
4135
4112
4066
4047
3992
3897
3821
1889
1854
901
876
Dahlöf B i sur. Lancet 2002;359:995-1003.
Losartan reduces more efectively stroke
with equal antihypertensive efficacy
Stroke with and without death
% of patients with the first stroke
8
7
Atenolol
6
5
Losartan
4
3
2
1
Months
Losartan
Atenolol
25%
Adjusted risk reduction
24.9%, p=0.001
Non-adjusted risk reduction 25.8%, p=0.0006
0
0
4605
4588
6
12
18
24
30
36
42
48
54
60
66
4528 4469 4408 4332 4273 4224 4166 4117 3974 1928 925
4490 4424 4372 4317 4245 4180 4119 4055 3894 1901 897
Dahlöf B i sur. Lancet 2002;359:995-1003.
Angiotensin receptor blockers and stroke risk
MOSES: ARB surpasses CCB for secondary
stroke prevention
N = 1405 with HTN and prior cerebral event
Primary
composite
outcome*
Fatal/nonfatal
CV events
Fatal/nonfatal
stroke
-25
-25
P = 0.061
P = 0.026
0
-5
-10
RRR Eprosartan
vs nitrendipine†
(%)
-15
-20
-25
-21
P = 0.014
-30
*Cerebrovascular, CV events, and all-cause death
†Events per 100 person-years, including recurrent events
Schrader J et al. Stroke. 2005;36:1218-26.
Meta-analysis of CV events with ARBs
vs comparators
Blood Pressure Lowering Treatment Trialists’ Collaboration
4 trials; N = 16,791
1.2
1.0
Relative risk of
event with ARB
vs comparator
0.8
0.6
Stroke
CHD
Heart failure Major CV event
BPLTTC. Lancet. 2003;362:1527-35.
LIFE: New Onset Diabetes
Intention-to-Treat
0.10
0.09
Atenolol
Endpoint Rate
0.08
0.07
0.06
Losartan
0.05
0.04
0.03
0.02
Adjusted Risk Reduction 25%, p<0.001
Unadjusted Risk Reduction 25%, p<0.001
0.01
0.00
Study Day
0
180
360
540
B Dahlof et al. Lancet 2002;359:995-1003
720
900
1080
1260
1440
1620
1800
1980
Cardiovascular death, stroke and
myocardial infarction in diabetics
24
Atenolol
% of patients with the
first onset of
complications
n= 139 (23%)
25%
20
16
Losartan
n= 103 (18%)
12
8
4
Adjusted risk reduction = 24,5%; p=0,031
Non- adjusted risk reduction = 26,7%; p=0,017
0
Months 0
6
Losartan (n) 586 569
Atenolol (n) 609 588
12
558
562
18
548
552
24
532
540
30
520
527
LH Lindholm, et al Lancet 2002; 359:1004-1010
36
513
507
42
501
486
48
484
472
54
459
434
60
237
204
66
127
99
LIFE: Diabetes Subgroup (n = 1195) Total Mortality
Proportion of patients, %
(secondary endpoint)
24
(from Lindholm LH et al., Lancet 359: 1004-1010,
2002)
20
Atenolol
RRR
16
39%
12
p = 0.002
Losartan
8
4
0
0
6
12
18
24
30
36
42
Study Month
48
54
60
66
The role and importance of
Losartan in the treatment of
diabetic nephropathy with
proteinuria
Effect of ACE Inhibition on Nephropathy
in Patients with Type 1 Diabetes
40
Captopril
Placebo
Progression
to death,
dialysis or
transplant
(%)
30
20
*
10
0
0
Collaborative Study Group
* p = 0.006 vs placebo.
1
2
Follow-up (y)
3
4
Lewis EJ et al. N Engl J Med 1993;329:1456-1462.
Effect of BP Reduction vs ACE Inhibition on Proteinuria
and Renal Function in Patients with Diabetes
Meta-regression analysis of 100 studies totaling 2,494 patients
with type 1 and type 2 diabetes.
* p < 0.05 vs calcium channel blockers.
† p < 0.05 vs control.
Kasiske BL et al. Ann Intern Med 1993;118:129-138.
Renal protection beyond RR ?
DHP- Ca Antag.
Other drugs
Risk
ESRF
ACEI
or
ARB
RR
DHP- Ca
Antag
ACEI or ARB
Dilation of
efferent
artheriole
RR
Dilation of
afferent
arteriole
RR
Ang II
Intraglomerular pressure
may stay unchanged
Ang II
Reduction of intraglomerular
pressure
Studies with ARBs in
diabetics
RENAAL (Reduction in Endpoints in NIDDM
with Angiotensin II Antagonist Losartan)
IDNT (Irbesartan in Diabetic Nephropathy
Trial)
IRMA2 (Irbesartan Micro-Albuminuria type 2
diabetes mellitus in hypertensive patients
RENAAL study
The Reduction of Endpoints in NIDDM with
the Angiotensin II Antagonist Losartan Study
Brenner BM et al. N Engl J Med 2001;
345(12):861-869.
Brenner BM et al J Renin-Angio-Aldo System 2000;1(4):328-335.
RENAAL
Progression of renal disease
p=0.01
18% reduction
dl/mg/year
-.08
-.06
-0.069
-0.056
-.04
-.02
0
Losartan
Brenner BM et al New Engl J Med 2001 ;345(12):861-869.
Placebo
RENALL – Results
Patients in the losartan group had a reduction in proteinuria
of 35%, while the patients in the placebo group had an
increase in proteinuria (P=<0.001)
Brenner et al. NEJM. 2001.
RENALL – Conclusions
• Losartan has renoprotective effects by
reducing risk of doubling creatinine AND
by reducing progression to ESRD
• Losartan reduces episodes of CHF
• Effects reported as independent of
blood pressure
ARBs decrease renal complications in T2DM
T2DM (N)
Treatment
IRMA-2
Microalbuminuria
(590)
Time to nephropathy:
Irbesartan
150/300 mg vs 39% (150 mg, P = 0.08)
placebo
70% (300 mg, P < 0.001)
IDNT
Nephropathy
(1715)
Irbesartan/
amlodipine/
placebo
ESRD/ Cr 2/mortality:
20% vs placebo (P = 0.02)
23% vs amlodipine (P = 0.006)
MARVAL
Microalbuminuria
(332)
Valsartan/
amlodipine
 UAER at 24 weeks:
44% valsartan vs 8% amlodipine
(P < 0.001)
RENAAL
Nephropathy
(1513)
Losartan/
placebo
ESRD/Cr 2 /all deaths:
16% vs placebo (P = 0.02)
Cr = creatinine
UAER = urinary albumin excretion rate
Primary outcome
Adapted from Sharma AM. Hypertension. 2004;44:12-19.
Combination treatment
• ACEI+ARB: different mechanisms of
action make combination treatment
useful owing to complete RAS
blockade,
CALM
(Candesartan And
Lisinopril
Microalbuminuria study)
Objectives:
To assess and compare the effects of candesartan or
lisinopril, or both, on blood pressure and urinary albumin
excretion in patients with microalbuminuria, hypertension,
and type 2 diabetes
Design:
12 weeks' monotherapy with candesartan or lisinopril
followed by 12 weeks' monotherapy or combination
treatment
199 patients aged 30-75 years
Candesartan 16 mg od or lisinopril 20 mg
Outcome:
Blood pressure and urinary albumin:creatinine ratio
CALM
Mean difference at week 24
Candesartan Lisinopril
Sitting DBP (mm Hg)
10.4
Combination
10.7
16.3
p=0.005
p=0.003
Sitting SBP (mm Hg)
14.1
16.7
p=0.02
25.3
39
p>0.20
50
p=0.002
Urinary albumin/
creatinine ratio (%)
Mogensen et al. BMJ 321; 1440
24
p=0.04
CALM
• Conclusions
– Candesartan 16 mg od has similar effect to
lisinopril on BP and microalbuminuria in
hypertensive patients with type 2 diabetes
– Combination treatment ACEI+ARB is more
effective than either monotherapy at reducing
BP and urinary albumin/creatinine ratio
Mogensen et al. BMJ 321; 1440
Pharmacokinetic differences between angiotensinconverting enzyme inhibitors and angiotensin
receptor blockers in renal failure
Parameter
ACE
inhibitors
Angiotensin receptor
antagonists
Proteinuria
↓↓
↓↓
Uric acid
↓
↓↓
Glomerular
filtration rate
↓↓
↓↓
Hyperkalemia
↑↑
↑
Blood pressure
reduction
↓↓
↓↓
Systemic
accumulation
Yes
No
AT2-receptor
stimulation
Possibly
↑↑
Renal and Pharmacokinetic Aspects of ACE
Inhibitor and Angiotensin Receptor Antagonist
Therapy in End-stage Renal Disease
Parameter
ACE
inhibitors
Angiotensin receptor
antagonists
Angioneurotic
edema
Yes
Yes, but much less frequently
Dialyzer reactions
Yes
No
Residual renal
function
↓↓
↓↓
Dialyzability
Yes
No
Hyperkalemia
↑↑
↑↑
Blood pressure
reduction
↓↓
↓↓
Systemic
accumulation
Yes
No
AT2-receptor
stimulation
Possibly
↑↑
Landmark studies with ACEI and ARBs and clinical
significance of RAAS blockade in hypertension, coronary
disease, MI and heart failure
ACEI in post-MI
> 100 000 patients !
Reduction of mortality (%)
35
29
30
27
22
25
19
20
12
15
10
7
5
0
ISIS-4 GISSI-3 SMILE SAVE
TRACE AIRE
ACEI in early phase AMI
• ACE inhibitors achieve a modest but
statistically significant reduction in
mortality ( 6% to 11%). Best results are
obtained in higher risk patients treated
long term, such as those with large
infarcts, in whom ACEI give a striking
reduction of 26% in mortality
ACE Inhibitors
• ACEI in patients with heart failure
reduce
– morbidity
– mortality
• ACEI in sedondary prevention of MI
reduce
–
– morbidity
– mortality
- development of HF
Studies: CONSENSUS, SOLVD, SAVE, AIRE,
ISSIS-4
ARBs and chronic
heart failure
®
Studies of ARBs in chronic
heart failure
ELITE
ELITE II
Val-HeFT
CHARM
ELITE study
• Application of 50 mg losartan, in
comparison with captopril, in
patients with heart failure
reduced mortality by 46% and
sudden cardiac death by 64%
ARBs and heart failure
• ARBs have been tested in an era when
ACE inhibitors were already the
established therapy of choise for heart
failure. Had the ARBs come earlier, they
would probably have been first choise.
Combination therapy with ACE
inhibitors and
ARB
• Adding the ARB to the ACEI gave better
results in more severe heart failure with the
mean ejection fraction about 25% (ValHeFT and CHARM trials). In diabetes and
diabetic renal disease, the combination is
advised when monotherapy fails to reduce
proteinuria sufficiently.
Indication and evidence for
combining ACEI and ARB
Indication
Indication for dual RAS inhibition
Hypertension
Not standard, possibly in LVH,
microalbuminuria, DM
Systolic heart failure
Yes, when symptoms persist despite
diuretic, beta blocker, and ACEI
Post myocardial infarction
No
Nephroprotection (diabetics)
Yes
Nephroprotection (non -diabetics)
Da
ONgoing Telmisartan
Alone and in combination
with Ramipril Global
Endpoint Trial
The telmisartan trial in cardiovascular
protection
Sponsored by Boehringer Ingelheim
Indication and evidence for
combining ACEI and ARB
Indication
Indication for dual RAS inhibition
Hypertension
Not standard, possibly in LVH,
microalbuminuria, DM
Systolic heart failure
Yes, when symptoms persist despite
diuretic, beta blocker, and ACEI
Post myocardial infarction
No
Nephroprotection (diabetics)
Yes
Nephroprotection (non -diabetics)
Yes
Less new diabetes
• An important finding with ACE inhibitors
and ARBs, especially when compared with
beta blockers or diuretics, is the decreased
developement of new diabetes.
Effect of ACEIs and ARBs on new-onset diabetes
Meta-analysis: 12 randomized controlled trials; N = 72,333 patients without
T2DM at baseline
Less likely to develop T2DM
More likely to develop T2DM
CAPPP
STOP-2
HOPE
LIFE
ALLHAT
ANBP2
SCOPE
ALPINE
CHARM
SOLVD
VALUE
PEACE
All pooled
ACEI pooled
ARB pooled
0.125
0.25
0.5
Relative risk (95% CI)
1
2
Abuissa H et al. J Am Coll Cardiol. 2005;46:821-6.
New-onset diabetes rate reduced by reninangiotensin-aldosterone system modulation
Risk of new-onset diabetes in hypertension:
comparison of antihypertensive drug classes
Drug related new diabetes
Inhibitors of renin-angiotensinaldosterone system
• Several analyses of retrospective clinical
trials suggest benefit of ACE inhibitors or
AT1 blockers in prevention of atrial
fibrillation, especially in patients with left
ventricular hypertrophy or dysfunction.
Atrial Fibrillation (AF) - Primary
Prevention
• In 2007 ESH / ESC guidelines recommendation to
preferentially use ARBs / ACEIs
• Evidence mainly from post-hoc analyses
Atrial Fibrillation
• In a meta-analysis on almost 12.000 patients with
systolic HF BBs were found to reduce (-27%) AF
• In patients with an AF history and systolic HF BBs
are a specific indication
Angiotensin receptor blockers in atrial
fibrillation: losartan versus atenolol
Pleiotropic effects of renin-angiotensin
system blockers
Inhibitors of renin-angiotensinaldosterone system
• Plasma aldosterone concentracions
increase in patients with atrial fibrillation
and atrial expression of the aldosterone
receptor is higher in these patients than
in those without the disorder.
Inhibitors of renin-angiotensinaldosterone system
• Patients with primary hyperaldosteronism
have a 12-fold greater risk of atrial
fibrillation than do controls matched for
blood pressure.
Inhibitors of renin-angiotensinaldosterone system
• Hence blockade of aldosterone receptors
could be a therapeutic option for patients
with atrial fibrillation, but data from trials
are not available.